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WIREs Nanomed Nanobiotechnol
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Aptamer‐functionalized hydrogels: An emerging class of biomaterials for protein delivery, cell capture, regenerative medicine, and molecular biosensing

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Abstract Molecular recognition is essential to the development of biomaterials. Aptamers are a unique class of synthetic ligands interacting with not only their target molecules with high affinities and specificities but also their complementary sequences with high fidelity. Thus, aptamers have recently attracted significant attention in the development of an emerging class of biomaterials, that is, aptamer‐functionalized hydrogels. In this review, we introduce the methods of incorporating aptamers into hydrogels as pendant motifs or crosslinkers. We further introduce the functions of these hydrogels in recognizing proteins, cells, and analytes through four applications including protein delivery, cell capture, regenerative medicine, and molecular biosensing. Notably, as aptamer‐functionalized hydrogels have the characteristics of both aptamers and hydrogels, their potential applications are broad and beyond the scope of this review. This article is categorized under: Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures Implantable Materials and Surgical Technologies > Nanomaterials and Implants Therapeutic Approaches and Drug Discovery > Emerging Technologies
Synthesis of aptamer‐functionalized hydrogels with aptamers as pendant motifs. (a) Polyacrylamide hydrogel synthesized by free radical polymerization. Adapted from Soontornworajit, Zhou, Shaw, et al. (2010). (b) Superporous hydrogel synthesized by free radical polymerization coupled with gas formation. Adapted from Abune et al. (2019). (c) Self‐assembly of aptamer‐functionalized fibrin hydrogel films. Aptamer‐fibrinogen conjugates (Ap‐Fg) were synthesized using a thiol‐ene reaction between thiol‐modified aptamers (Ap) and acrylate‐modified fibrinogen (Fg). Adapted from Zhao, Coyne, et al. (2019). (d) Dual aptamer‐patterned hydrogel film formed by a UV‐light mediated thiol‐ene reaction. Adapted from Z. Zhang, Liu, et al. (2018). (e) Entrapment of aptamer‐functionalized particles in agarose hydrogel. Adapted from Soontornworajit, Zhou, and Wang (2010)
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Aptamer‐functionalized hydrogels for visual biosensing. (a) Logic‐gated hydrogels for gold nanoparticle (AuNP) release. AND‐gated hydrogels are crosslinked with an aptamer linker containing both cocaine and ATP sequences, while OR‐gated hydrogels are crosslinked with a nonfunctional DNA linker complementary to the cocaine and ATP responsive aptamers. Adapted from Yin et al. (2012). (b) Aptamer‐crosslinked hydrogels for enzyme‐based colorimetric conversion. Target‐mediated hydrogel dissolution triggers the production of an iodine (I2) solution, forming a semi‐quantitative color gradient. Adapted from Tian et al. (2016). (c) Multi‐target point‐of‐care testing device utilizing aptamer‐crosslinked hydrogels as flow regulators. Target molecules present in the sample inhibited hydrogel formation allowing sample fluid to flow through the dye‐containing layer for visual detection. Adapted from X. Wei et al. (2015)
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Aptamer‐functionalized hydrogels for electrochemical biosensing. (a) Aptamer‐functionalized hydrogel‐coated electrode surface for immobilizing magnetic nanoparticles. Dual thrombin aptamers (TBA1 and TBA2) enable thrombin (TB) capture and magnetic nanoparticle (MNP) tagging for signal amplification. DPV, differential pulse voltammetry. Adapted from X. Wang, Gao, et al. (2019). (b) Target‐induced hydrogel formation on an electrode surface. Heparanase (HPA) aptamers regulate the assembly of DNA‐grafted polymers triggering an impedimetric signal shift. Adapted from Z.‐H. Yang et al. (2017)
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Aptamer‐functionalized hydrogels for fluorescent biosensing. (a) Pendant aptamers stained with SYBR Green I due to Hg2+‐induced reconfiguration of aptamers. Adapted from Dave et al. (2010). (b) Proximity‐mediated fluorescent quenching of aptamer‐crosslinked DNA‐grafted polymers. Left: hydrogel coating of silica nanoparticles (SiNPs) resulting in fluorescence resonance energy transfer (FRET) inhibition of FAM by Cy3; right: intracellular ATP‐triggered hydrogel dissociation for FAM restoration. Adapted from Ji et al. (2019). (c) Aptamer‐triggered assembly of fluorescent DNA hydrogels via rolling circle amplification (RCA). OTA, ochratoxin A. Adapted from Hao et al. (2020)
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Cell capture for regenerative medicine application. (a) Concept of aptamer‐mediated cell adhesion and biophysical signal transduction. Adapted from N. Chen et al. (2012). (b) Aptamer‐bilayer scaffolds were able to specifically recognize and capture MSCs, leading to enrichment of MSCs around the osteochondral defect and their directional differentiation for knee repair. Adapted from X. Hu et al. (2017). (c) Aptamer‐functionalized hydrogels (Apt+) effectively recruited MSCs in vivo and achieved a better outcome of cartilage repair than the control and the scaffold only (Apt−) in an osteochondral defect model. Adapted from X. Wang, Song, et al. (2019)
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Regenerative medicine application of sustained protein delivery. (a) VEGF release from aptamer‐functionalized fibrin hydrogels (Ap‐Fn) significantly reduced skin wound size compared to scrambled aptamer‐functionalized fibrin hydrogels (Sc‐Fn) and fibrin hydrogels (Fn). Adapted from Zhao, Coyne, et al. (2019). (b) Ap‐Fn loaded with 10 μg/ml VEGF exhibited a moderate increase in post‐operative bone healing in critical sized cranial defect compared to all other treatment groups. Adapted from Juhl et al. (2019). (c) Dual protein delivery from aptamer‐functionalized hydrogels promoted vascularization in chicken embryo chorioallantoic membrane. Adapted from Abune et al. (2019)
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Synthesis of aptamer‐functionalized hydrogels with aptamers as crosslinkers. (a) Crosslinking of DNA‐grafted polymer chains. Adapted from H. Yang et al. (2008). (b) Crosslinking of Y‐shaped DNA nanoscaffolds via “stick end” hybridization. Adapted from L. Zhang et al. (2013)
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Drosera‐inspired bifunctional hydrogel for diseased cell catch and kill. The hydrogel consists of two layers. The top layer is functionalized with aptamers that can catch target cells. The bottom layer is functionalized with double stranded DNA to retain toxic drugs for killing captured cells. This bifunctional hydrogel can be regenerated for continuous cell catching and killing. Adapted from S. Li et al. (2015)
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Programmable cell capture and release. (a) Regenerable hydrogel for cyclic cell catch and release using DNA hybridization. Cell release can be triggered by complementary sequence strand displacement. Adapted from Z. Zhang et al. (2012). (b) Endonuclease‐responsive aptamer hydrogels for circulating tumor cells (CTCs) catch and release. Adapted from S. Li et al. (2013). (c) Cell capture via hybridization chain reaction and ATP‐triggered molecular reconfiguration. Adapted from Song et al. (2017)
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Aptamer‐functionalized hydrogels for sustained, triggered, and self‐programmed protein release. (A). Illustration of sustained protein release from aptamer‐functionalized hydrogel and release profile of PDGF‐BB from blank hydrogels, low affinity, and high affinity aptamer‐functionalized hydrogels. Adapted from Soontornworajit, Zhou, Shaw, et al. (2010). (b) Illustration of triggered protein release and sequential protein release from single and dual aptamer‐functionalized hydrogels. CS, complementary sequence. Single: adapted from Battig et al. (2014); dual: adapted from Battig et al. (2012). (c) Self‐programmed protein release by sequential DNA displacement, and hybridization. The binding of a triggering small molecule (TM) (e.g., adenosine) to the responsive aptamer sequence (AA) frees the triggering DNA sequence (TS) to bind to an aptamer sequence binding to the target protein (AP). The treatment of hydrogels with adenosine (+) triggered the release of PDGF‐BB. Adapted from Lai, Li, et al. (2017)
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Therapeutic Approaches and Drug Discovery > Emerging Technologies
Implantable Materials and Surgical Technologies > Nanomaterials and Implants
Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures

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